Dementia is among the most debilitating disorders affecting the elderly. The majority of cases are caused by Alzheimer's disease (AD), which is characterized by senile plaques, neurofibrillary tangles, and loss of synapses. Despite their rapidly increasing prevalence within the aged population, progress in understanding the etiology and pathogenesis of these diseases, and developing therapies for them, has been severely hampered by the lack of suitable animal models. Further, microvascular disease is a common finding in the aged brain and it may precede the development of dementia. The ApoE4 gene is a predisposing factor for various types of vascular pathology as well as an important risk factor for the development of sporadic AD. The autosomal dominant disorder CADASIL, which results from mutations in the Notch3 gene, is a brain microvascular disease causing stroke and dementia and is characterized by thickening of the smooth muscle layer of brain arterioles. Agrin, a synapse organizing molecule in the peripheral nervous system, is expressed in normal brain but its function there remains unknown. In the central nervous system, it is found in neurons as well as within the basement membranes of the capillaries that form the blood brain barrier. Recent studies from two members of the project (Fallon and Stopa) have shown agrin redistributes to the Abeta-containing senile plagues and becomes insoluble in AD brains. These patients also exhibit fragmentation on the agrin-containment basement membranes of the brain microvasculature. In this proposal we will use tissue-specific targeted disruption of the agrin gene as a tool to study agrin function at synapses in normal brain (Aim #1) and in mouse models of AD (Aim #2). We will also examine the status of the microvasculature in mouse models of AD as well as in ApoE4 homozygous animals, particularly with respect to agrin expression in the basement membrane. Finally, we will generate mouse models of CADASIL (Aim #3) by 'knocking-in' mutant Notch3 alleles. We will characterize the microvasculature in these animals for comparison with CADASIL patients. We will also determine the prevalence of dominant Notch3 mutations in patients demonstrating MRI evidence of the CADASIL phenotype.